Angiogenesis is a process wherein new capillary vessels are formed from the existing microvessels, and angiogenesis normally occurs during embryonic development, tissue regeneration and wound healing, corpus lutem development which is periodic change in female reproductive system, and even in this case, angiogenesis is stringently controlled and progressed (Folkman J et al., Int. Rev. Exp. Pathol., 16, pp 207-248, 1976).
In the adult, vascular endothelial cells grow very slowly, and relatively do not divide well compared to other kinds of cells. The process of angiogenesis generally consists of decomposition of vascular basement membrane due to protease by stimulation of angiogenesis promoter, migration of vascular endothelial cells, proliferation, and tube formation by differentiation of vascular endothelial cells to reconstitute blood vessels to produce new capillary vessels.
There are diseases caused by failing to self-regulation of angiogenesis and abnormal growth. The diseases related to angiogenesis occurring at pathological states include hemangioma, vascular fibroma, vascular malformation, and cardiovascular disease such as atherosclerosis, vascular adhesion, scleroderma, and ophthalmic diseases caused by angiogenesis include angiogenesis due to corneal transplantation, neovascular glaucoma, diabetic retinopathy, corneal disease caused by angiogenesis, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasias, granular conjunctivitis, and the like.
Chronic inflammatory diseases such as arthritis, dermatological diseases such as psoriasis, capillarectasia, pyogenic granuloma, seborrheic dermatitis, acne, Alzheimer's diseases and obesity are also related to angiogenesis, and cancer growth and metastasis are necessarily dependent upon antiogenesis (D'Amato R J et al., Ophthalmology, 102(9), pp 1261-1262, 1995; Arbiser J L, J. Am. Acad. Dermatol., 34(3), pp 486-497, 1996; O'Brien K D et al. Circulation, 93(4), pp 672-682, 1996; Hanahan D et al., Cell, 86, pp 353-364, 1996).
Particularly, in cancer, angiogenesis plays an important function for cancer cell growth and metastasis. Tumor is supplied with nutrient and oxygen required for growth through angiogenesis, and angiogenetic blood vessels penetrated into tumor provide a pathway for cancer cells to enter into blood circulation system thereby allowing metastasis of cancer cells (Folkman and Tyler, Cancer Invasion and metastasis, Biologic mechanisms and Therapy (S. B. Day ed.) Raven press, New York, pp 94-103, 1977; Polverini P J, Crit. Rev. Oral. Biol. Med., 6(3), pp 230-247, 1995).
To the contrary, although excessive formation of blood vessels sometime becomes a leading cause of worsening of diseases, non-formation of blood vessels also becomes a cause of serious diseases. Angiogenesis is essential phenomenon for wound healing or tissue regeneration, for example, placenta with undeveloped blood vessel formation is an important cause of miscarriage, and necrosis, ulcer and ischemia due to non-formation of blood vessel may induce abnormal function of tissues or organs or may become a cause of death. And, diseases such as atherosclerosis, myocardial infarction and angina pectoris also become a cause of slow blood supply. Accordingly, there is a need for development of a treatment method that may decrease tissue damage due to low oxygen or low nutrition state caused by non-formation of blood vessels, and induce or promote new blood vessel formation for smooth tissue regeneration.